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However, several issues can affect its effectiveness and bioavailability when administered orally, including low solubility and uncontrolled release. The primary aim of this study is to develop a hydrogel containing LTZ-loaded invasomes (LLI). This formulation is designed to enhance LTZ\u2019s sustainability, permeability, targeting, bioavailability, and efficacy as a potential treatment for BC. The optimized LLI formulation was established by evaluating various formulations using the Box-Behnken design, focusing on entrapment efficiency and particle size. The LLI hydrogel was created by combining this optimal formulation with 2% Carbopol and was characterized in vitro for viscosity, release kinetics, and permeation. The anti-cancer effects, targeting ability, and safety of the LLI hydrogel were assessed in vivo using the 7,12-dimethylbenz(a)anthracene-induced breast cancer rat model (DIBC). The selected LLI formulation contained 3% phospholipids, 2% ethanol, and 0.5% cineole. Compared to free LTZ, the LLI hydrogel improved LTZ sustainability and permeation by 61.58% and 3.55-fold, respectively. Additionally, the LLI hydrogel reduced tumor volume by 99.69% compared to the DIBC group. Moreover, the concentration of LTZ accumulated in the tumor was 9.36 times greater in the LLI hydrogel than in the oral LTZ group. The transdermal LLI hydrogel represents a promising and safe treatment option for BC.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04634-6","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T10:35:19Z","timestamp":1760351719000},"page":"4011-4026","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Improving the efficacy and targeting of letrozole for the control of breast cancer: in vitro and in vivo studies"],"prefix":"10.1007","volume":"399","author":[{"given":"Shahira F. 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